G-protein coupled receptors mediate intercellular signaling by a vast array of neurotransmitters, modulators and hormones. They provide sites t which drugs can be used to modulate signaling in particular pathways and an entrance into study of the physiology of the systems in which they are functional links. A recently identified subfamily of G-protein coupled receptors (referred to as the secretin- VIP family based on two initially identified members) has virtually no identifiable amino acid sequence conservation with the majority of G-protein coupled receptors (the rhodopsin family). Much less is known about structure function relationships and effector system coupling of the secretin-VIP family receptors. Their cloning has also raised new questions about their physiological roles and created tools for study of their distribution, regulation and pharmacology. We used degenerate PCR primers based on conserved sequences in the receptors for secretin, VIP and PTH to screen nervous system derived cDNA libraries for related sequences. Previously we identified the receptor for GIP (gastric inhibitory peptide, or glucose-dependent insulinotropic peptide), which was not previously known to be in the brain. We have now identified a novel second receptor for VIP. The VIP2 receptor appears to mediate VIP's effects in the thalamus, hypothalamus, and several peripheral organs including the pituitary.